@article{a9060f2543e643d68a0549af5360220e,
title = "Prioritization and association analysis of murine-derived candidate genes in anxiety-spectrum disorders",
abstract = "Background: Anxiety disorders are common psychiatric conditions that are highly comorbid with each other and related phenotypes such as depression, likely due to a shared genetic basis. Fear-related behaviors in mice have long been investigated as potential models of anxiety disorders, making integration of information from both murine and human genetic data a powerful strategy for identifying potential susceptibility genes for these conditions. Methods: We combined genome-wide association analysis of fear-related behaviors with strain distribution pattern analysis in heterogeneous stock mice to identify a preliminary list of 52 novel candidate genes. We ranked these according to three complementary sources of prior anxiety-related genetic data: 1) extant linkage and knockout studies in mice, 2) a meta-analysis of human linkage scans, and 3) a preliminary human genome-wide association study. We genotyped tagging single nucleotide polymorphisms covering the nine top-ranked regions in a two-stage association study of 1316 subjects from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders chosen for high or low genetic loading for anxiety-spectrum phenotypes (anxiety disorders, neuroticism, and major depression). Results: Multiple single nucleotide polymorphisms in the PPARGC1A gene demonstrated association in both stages that survived gene-wise correction for multiple testing. Conclusions: Integration of genetic data across human and murine studies suggests PPARGC1A as a potential susceptibility gene for anxiety-related disorders.",
keywords = "Anxiety disorder, candidate gene, data integration, depression, genetic association, internalizing",
author = "Hettema, {John M.} and Webb, {Bradley T.} and Guo, {An Yuan} and Zhongming Zhao and Maher, {Brion S.} and Xiangning Chen and An, {Seon Sook} and Cuie Sun and Aggen, {Steven H.} and Kendler, {Kenneth S.} and Kuo, {Po Hsiu} and Takeshi Otowa and Jonathan Flint and {Van Den Oord}, {Edwin J.}",
note = "Funding Information: This work was supported by National Institutes of Health Grant R21MH79192 (JMH). The National Institute of Mental Health (NIMH) Control Samples were from the National Institute of Mental Health Schizophrenia Genetics Initiative (NIMH-GI) and collected under the Molecular Genetics of Schizophrenia (MGS) collaboration. Funding support for these samples was provided by the Genomics Research Branch at the NIMH, and the genotyping and analysis of samples was provided through the Genetic Association Information Network (GAIN) and under the MGS U01s: MH79469 and MH79470. Assistance with data cleaning was provided by the National Center for Biotechnology Information. Samples and associated phenotype data for the MGS genome-wide association study were collected under the following grants: NIMH Schizophrenia Genetics Initiative U01s: MH046276 (C.R. Cloninger), MH46289 (C. Kaufmann), and MH46318 (M.T. Tsuang); and MGS Part 1 (MGS1) and Part 2 (MGS2) R01s: MH67257 (N.G. Buccola), MH59588 (B.J. Mowry), MH59571 (P.V. Gejman), MH59565 (Robert Freedman), MH59587 (F. Amin), MH60870 (W.F. Byerley), MH59566 (D.W. Black), MH59586 (J.M. Silverman), MH61675 (D.F. Levinson), and MH60879 (C.R. Cloninger). Genotype data for the early release data used in our gene ranking scheme were generated at the Center for Genotyping and Analysis at the Broad Institute of Harvard and Massachusetts Institute of Technology as part of a multi-institutional collaborative research study (principal investigators: Pamela Sklar, M.D., Ph.D.; Jordan Smoller, M.D., Sc.D.; Vishwajit Nimgaonkar, M.D., Ph.D.; and Edward Scolnick, M.D.). The MGS nonGAIN dataset used for the replication analysis described in Supplement 1 were obtained from the database of Genotype and Phenotype found at http://www.ncbi.nlm.nih.gov/gap through database of Genotype and Phenotype accession numbers phs000167.v1.p1. We thank Alex Putnam, Ph.D., and Michael Miles, M.D., Ph.D., for useful discussions regarding their mouse data (not included in the current study). We acknowledge the contribution of the Virginia Twin Registry, now part of the Mid-Atlantic Twin Registry, for the ascertainment of subjects for this study. The Mid-Atlantic Twin Registry is currently supported by UL1RR031990 from the National Center for Research Resources . Carol Prescott, Ph.D., provided critical help in the collection of the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders sample. We also wish to thank Youfang Liu, Ph.D., and Patrick Sullivan, M.D., (University of North Carolina, Chapel Hill) for providing imputed genotypes for the nonGAIN sample used in our replication analysis. ",
year = "2011",
month = nov,
day = "1",
doi = "10.1016/j.biopsych.2011.07.012",
language = "English (US)",
volume = "70",
pages = "888--896",
journal = "Biological Psychiatry",
issn = "0006-3223",
publisher = "Elsevier USA",
number = "9",
}